Is liver transplantation an appropriate treatment for acute alcoholic hepatitis?
Article Outline
In 1961, Beckett, Livingstone and Hill described a condition they called ‘acute alcoholic hepatitis’ [1]. They reported seven alcoholic patients in whom jaundice developed after sustained consumption of alcohol. The accompanying syndrome included abdominal pain, fever, anorexia and leukocytosis. The authors reviewed liver tissue from six of their cases and found that cirrhosis or fibrosis, acute inflammatory infiltration of the lobule, Mallory's hyaline, hepatocyte degeneration and necrosis were common but not invariable features in biopsy or necropsy tissue. Since then, the syndrome of acute alcoholic hepatitis has become a well-recognized part of the clinical spectrum of alcoholic liver disease. However there is an important difference the way the phrase ‘acute alcoholic hepatitis’ is used by clinicians and pathologists. Clinicians intend ‘acute alcoholic hepatitis’ to mean the syndrome described by Beckett and co-workers, whereas the pathologists have come to use the term as a descriptor of the histopathologic constellation of features outlined above, without requiring the presence of the clinical syndrome.
In the past 5 years studies in small animal models have elucidated many of the mechanisms which underlie the development of the clinico-histopathological entity of acute alcoholic hepatitis. Key elements include the generation of reactive oxidative species by ethanol, the activation of kupffer cells through nuclear factor kappaB, and the expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF) alpha [2], [3], [4]. These data are supported by studies in humans that confirm that acute alcoholic hepatitis is accompanied by increased oxidative stress and increased circulating TNF alpha [5], [6].
Abstinence from alcohol is the only therapy that consistently improves outcome from acute alcoholic hepatitis [7]. Unfortunately, even when patients adhere to this advice, recovery is not guaranteed and many patients die. The outcome of acute alcoholic hepatitis is dictated by the severity of the clinical syndrome. This was recognized by Maddrey and colleagues who developed a discriminant function based on measurements of serum bilirubin and prothrombin to stratify patients with acute alcoholic hepatitis into high and low risk groups [8]. Patients whose Maddrey score (4.6 (prothrombin time−control time)+serum bilirubin [in μmol/l]/17.1} exceeds 32 have a high immediate mortality. For example, short-term mortality in two placebo-controlled trials restricted to patients with acute alcoholic hepatitis and a high Maddrey score (>32) was 35 and 46.1% in the respective placebo cohorts [8], [9]. Mutimer et al. showed that the addition of acute renal failure worsens the prognosis of acute alcoholic hepatitis further so that almost all patients in their series requiring dialysis died [10].
Fulton and McCullough have reviewed treatment of alcoholic hepatitis [11]. Among the therapeutic agents they discuss are corticosteroids, amino acid supplements, insulin/glucagon infusions, propylthiouracil, anabolic steroids, colchicine, polyunsaturated lecithin, S-adenosyl-l-methionine, calcium channel blockers and pentoxifylline. Of these therapies, only corticosteroids have found a place in regular practice, although even here, the data on their efficacy are controversial [12]. Recently, Reynolds and his group have presented interesting data using pentoxifylline in acute alcoholic hepatitis [9]. Pentoxifylline is attractive because it reduces the expression of TNF alpha, thereby providing a rationale for its use in acute alcoholic hepatitis. It is administered per orem, and appears to have few significant side effects. They found a reduction of short-term mortality from 46.1% in the 52 patients who received placebo to 24.5% among the 49 patients who received pentoxifylline.
Such high mortality even among abstinent patients with access to the best care inevitably leads to the question whether liver transplantation would improve the outcome for patients in whom liver function is severely impaired due to acute alcoholic hepatitis. Assessment of the potential benefit of transplantation for patient with acute alcoholic hepatitis has to take in to consideration the potential salutary effect of withdrawal of alcohol. Despite this caveat, the data of Poynard suggest that liver transplantation is beneficial when applied to alcoholics with decompensated liver failure [13]. In the past acute alcoholic hepatitis has been considered an inappropriate indication for liver transplantation. Most programs in North America and Europe have required a period of abstinence before admitting alcoholic patients to transplantation [14], [15]. By definition, patients with acute alcoholic hepatitis have been drinking to excess in the recent past and have been excluded thereby. The rationale for a period of abstinence has included the fear that the recent drinker will relapse to alcohol excess after transplantation. While isolated cases of relapse with consequent damage to the graft are recorded, most studies have found that alcoholism relapse leading to allograft injury is a relatively unusual complication among those patients with alcoholism who are selected for liver transplantation [16], [17]. Furthermore, most studies have not shown a direct relationship between the interval of abstinence prior to transplantation and the likelihood of alcohol relapse after transplantation [17]. Data on transplantation among patients with the clinical syndrome of acute alcoholic hepatitis are scanty, mainly because most programs have excluded these patients from consideration.
An alternative rationale for adhering to a prescribed period of abstinence was advanced when minimal criteria for placement on the transplant waiting list were drawn up in the US: namely the interval is necessary to allow those patients with acute alcoholic hepatitis to recover [18]. It is likely that this policy will face new challenges in the US on account of the decision to change the method to allocate donor livers [19]. The purpose of the change is to diminish the importance of waiting time as an arbiter of allocation between potential recipients. The present system uses Child-Turcotte-Pugh (CTP) class to stratify patients according to severity of liver failure, and uses time on the waiting list to decide a tie. The new system will attempt to have a more gradual and extended scale of severity, and avoid the need to use waiting time as a deciding factor. The Model for End-stage Liver Disease (MELD) prognostic score has been chosen to replace CTP class [19]. This scoring system uses serum bilirubin, creatinine and prothrombin time-internationalized normalized ratio. As I have pointed out already, patients with severe acute alcoholic hepatitis, as shown by elevated serum bilirubin and prothrombin time and especially those with acute renal failure, have the worst prognosis for medical management. However, these are the very patients who will score highly on MELD. Thus, the most severely ill patients with acute alcoholic hepatitis would, if placed on the transplant waiting list, likely take precedence over other patients on the list. If placed on the list they would put a new pressure on the consensus which requires a period of abstinence before permitting transplantation, since this policy ensures that some patients with acute alcoholic hepatitis should be allowed to die rather than first being offered a liver transplant. In addition, the growing use of live liver donors, usually related to the recipient, will inevitably lead to requests from families to donate to a family member with acute alcoholic hepatitis, irrespective of the cadaveric waiting list.
What then should our response be to a renewed interest in offering liver transplants to patients with acute alcoholic hepatitis? As noted by the recent workshop on transplantation for alcoholic liver diseases, data on the benefit if any of transplantation in patients with acute alcoholic hepatitis are inadequate [20]. Small single center series have been reported which lack adequate numbers, are compromised by retrospective design and inadequate follow-up. It is clear that some liver transplants in patients with acute alcoholic hepatitis have been successful [10], [21]. The risk of alcoholic relapse in these patients has not been adequately studied. The ideal answer to this dilemma would be a randomized controlled clinical trial of liver transplantation in patients with acute alcoholic hepatitis. In the absence of such data, two recent papers in the Journal offer insight into the potential role for liver transplantation in treating acute alcoholic hepatitis. First, Veldt and co-workers raise the question about how many patients with alcoholic liver disease including acute alcoholic hepatitis would be suitable for liver transplantation [22]. They noted a discrepancy between the great numbers of patients dying in France of acute decompensation of alcoholic liver disease, and the comparatively small number of such patients being transplanted. They gathered prospective data on 74 new hospital admissions with alcoholic liver disease and followed them for up to 3 years. Fifty-seven (76%) patients died in follow-up. Nineteen patients died during the initial admission, five were lost to follow-up and only 12 are known to be alive on completion of the study. Main causes of death were hepatorenal syndrome, all of whom died, liver failure, infection, and hemorrhage. Thirteen patients had acute alcoholic hepatitis, of whom seven recovered with medical management with or without corticosteroids. Only two patients were transplanted. Among the cohort as a whole, ‘alcohol consumption during follow-up remained the strongest independent factor predicting survival’. When prognostic factors were looked for in the sub-group who survived the initial hospitalization, alcohol consumption during follow-up, hyponatremia and hypercreatinemia were the independent predictive factors. These data confirm three important observations relevant to the discussion on liver transplantation in decompensated alcoholic liver disease. First, the mortality when these patients are managed medically is high. Second, a significant number of patients with the clinical syndrome of acute alcoholic hepatitis will recover with medical management. Third, continued alcohol use is an important contributor to mortality in the period after initial admission to hospital. The authors found that clinical signs of recovery from liver injury tend to occur within 3 months of initiation of abstinence. The authors conclude that few patients will come to transplant because they will die first or return to alcohol, but that transplantation should be considered among those patients in whom decompensation persists despite 3 months abstinence.
In the present issue of the Journal, Tomé et al. consider the influence of acute alcoholic hepatitis, defined in pathological terms, on outcome after liver transplantation [23]. They report a retrospective review of 68 consecutive patients transplanted for alcoholic cirrhosis in the absence of viral hepatitis. All had a minimum of 3 months abstinence prior to transplantation, thereby meeting the screening time interval suggested by Veldt et al. It is important to point out that this criterion probably excluded many patients with the clinical acute alcoholic hepatitis syndrome. The explanted liver was reviewed in a blinded fashion, and superimposed alcoholic hepatitis was observed in 36. This was characterized, using Maddrey score, as severe hepatitis in ten subjects and mild in 26. The presence of acute alcoholic hepatitis on biopsy did not influence survival after transplantation, when compared to alcoholics without acute hepatitis, or non-alcoholics transplanted in the same time period. Similarly, there was no difference in survival between those with severe and mild acute alcoholic hepatitis. Finally, the presence of acute alcoholic hepatitis on biopsy was not associated with a greater frequency of alcoholic relapse after transplantation.
While these two studies do not answer all outstanding questions about the potential role for transplantation in managing acute alcoholic hepatitis, they offer a way forward. They suggest that liver transplantation may be appropriate for some patients, even after a period of abstinence to assess the chance for spontaneous recovery. The data also indicate that we lack the evidence to say whether liver transplantation will or will not help acute alcoholic hepatitis patients. It would appear that the time is right for controlled prospective randomized data. A reasonable approach would be a randomized trial of liver transplantation compared to medical management in patients with severe acute alcoholic hepatitis which has persisted despite full medical management including abstinence of 3 months to allow recovery where possible. It will be only after such a trial that a definitive answer regarding the role of liver transplantation in treating acute alcoholic hepatitis can be given.
References
- . Acute alcoholic hepatitis. Br Med J. 1961;ii:1113–1119
- Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology. 1999;117:942–952
- Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology. 1999;30:934–943
- Delivery of IkappaB superrepressor gene with adenovirus reduces early alcohol-induced liver injury in rats. Hepatology. 2001;34:1149–1157
- . Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. Hepatology. 1991;13:267–276
- Alcohol-induced generation of lipid peroxidation products in humans. J Clin Invest. 1999;104:805–813
- . Natural history of alcoholic hepatitis 11. The long-term prognosis. Am J Gastroenterol. 1971;56:515–525
- Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med. 1989;110:685–690
- . Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119:1637–1648
- Managing severe alcoholic hepatitis complicated by renal failure. Q J Med. 1993;86:649–656
- . Treatment of alcoholic hepatitis. In: Clinics in liver disease. Philadelphia: Saunders WB; 1998;p. 799–819
- . Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables. Gut. 1995;37:113–118
- Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. J Hepatol. 1999;30:1130–1137
- . Liver transplantation for alcoholic liver disease: a survey of transplantation programs in the United States. Liver Transpl Surg. 1997;3:220–226
- . Transplantation for alcoholic liver disease: a perspective from Europe. Liver Transpl Surg. 1998;4:S51–S57
- Rapidly progressive liver injury and fatal alcoholic hepatitis occurring after liver transplantation in alcoholic patients. Transplantation. 1999;67:1562–1568
- . Liver transplantation in the alcoholic patient. In: Maddrey WC, Sorrell M, Schiff E editor. Transplantation of the liver. 3rd ed. Lippincott: Williams and Wilkins; 2000;
- Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg. 1997;3:628–637
- . Predicting the prognosis of chronic liver disease: an evolution from child to MELD. Hepatology. 2001;33:473–475
- Transplantation for alcoholic liver disease. J Hepatol. 2002;36:130–137
- . Survival and quality of life after liver transplantation for acute alcoholic hepatitis. Liver Transpl Surg. 1997;3:240–244
- Indication for liver transplantation in severe alcoholic cirrhosis: quantitative evaluation and optimal timing. J Hepatol. 2002;36:93–98
- Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease. J Hepatol. 2002;36:793–798
PII: S0168-8278(02)00086-7
© 2002 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
